Glen St. Mary was voted Florida's Outstanding Rural Community in 2004. The first permanent white settlers arrived in 1829 but the town wasn't officially a township until 1881. The Timucuan had inhabited the area up into the early 1700's, then were replaced by Creeks and Seminoles. Daniel Mann and his wife, LeVicy, moved in among the natives in 1829. Another settler who arrived that year didn't survive to the end of the year: killed in an early morning Indian attack. Other settlers came and went but the white population didn't really start to grow until the area got into growing cotton. Cotton flourished until the Civil War, then the fields were abandoned.

For about 15 years after the war, the only activity in the area revolved around timber operations. Then a stockbroker from Chicago arrived and purchased about 1,600 acres of abandoned cotton fields and began the Glen St. Mary Nursery Company (which is still in business). In the late 1890's a disastrous freeze nearly wiped out the agricultural businesses previously flourishing in the area but that freeze also stimulated the owner of the Nursery Company to do the research necessary to grow his business to the point where he was exporting plants to South and Central America, India, Russia, China and Spain. Most of the citrus industry that now exists in the Rio Grande Valley of Texas is based on stock that came from the Glen St. Mary Nursery Company. Then came Alverdo Geitgey, Baker County's first real estate developer.

The population of Glen St. Mary is down more than 7% since 2000.